Once gases reach the alveolar parenchyma by ventilation, absorption into the blood or excretion from it occurs not by convection, but by molecular diffusion according to a physiological restatement of Ohm’s law (Fig. 9.1). Diffusion of any gas through the septal barrier and into the blood is proportional to the alveolar epithelial surface area (S_A) and the alveolar capillary endothelial surface area (S_C) comprising the membrane available for such exchange. Quantitative measurements on electron photomicrographs of normal lung have estimated S_A and S_C to each be 50-70 m². This symmetry of S_A and S_C dimensions is perhaps not surprising, given the importance placed earlier on good V̇_A/Q̇ matching. Alveolar diffusion of any gas is inversely proportional to septal barrier thickness, estimated as its harmonic mean (τ_S) to emphasize statistically the thinnest regions where diffusion is presumably favored.

Given these lung anatomical features that affect all gases, other factors will determine whether diffusional equilibrium is achieved between an alveolar airspace and the blood flowing through its capillaries. Again by analogy to Ohm’s law, each gas diffuses proportionally to the pressure gradient between its “source” (P₁, the higher value) and its “sink” (P₂, the lower value). For O₂, P₁ = P_Ao₂ (Chap. 8) and P₂ = P_V̄o₂ as measured by a pulmonary artery catheter, yielding a normal inwardly directed gradient of ~60 mm Hg on room air. That gradient is dramatically affected by both F_Io₂ and P_B insofar as those affect P_Io₂ and thus P_Ao₂. For CO₂, P₁ = P_V̄co₂, and P₂ = P_Aco₂ (= P_aco₂), for a normal outwardly directed gradient of 5-6 mm Hg and one that is less sensitive to F_Io₂ or P_B than that for Po₂. Indeed, data in Table 3.2 were used to make this point earlier of a tenfold larger gradient for O₂ despite that the flow of CO₂ outward and O₂ inward are nearly the same. How can this occur? Gases will diffuse at different rates, despite equal values for S_A, S_C, τ_S, and (P₁-P₂), because of differing coefficients of diffusivity (D), defined as the solubility of a gas in aqueous media divided by its mass-dependent rate of gaseous-free diffusion. The value of D for CO₂ is ~20 times that of O₂ in biological systems, implying that lung disorders will present more often with hypoxemia (low blood O₂ content) than with hypercarbia (high blood CO₂ content). One can also appreciate that alveolar diffusion of all gases will diminish in a disease like emphysema where S_A and S_C are decreased (Fig. 9.2). Likewise, alveolar diffusion decreases in those diseases for which τ_S is increased, for example during the edema of acute lung injury (Chap. 28) or after the development of fibrosis in some interstitial lung diseases that show a restrictive pattern by pulmonary function test (PFT) (Chap. 24).

Given this discussion, what time constraints exist on gas diffusion in the lung? This question can be answered by considering capillary transit times of erythrocytes in the lung in relation to the equilibration rate of alveolar gases with the interiors of those red blood cells (RBCs) (Fig. 9.3). An RBC spends ~0.8 seconds in an alveolar capillary at a resting Q̇ but less than 0.3 seconds when Q̇ approaches maximal values. The long RBC transit time at low Q̇ is usually sufficient for N₂O (an anesthetic gas), CO, CO₂, and O₂ to equilibrate across the alveolar-capillary barrier, that is, P₁ ≅ P₂ for these gases near the venular end of alveolar capillaries. By example, N₂O is very soluble in blood but does not bind to Hb. Thus, it equilibrates across the barrier regardless of the original (P_An₂o-P_c’n₂o) or transit time, so that its absorption is perfusion limited only by Q̇. If Q̇ increases, then N₂O uptake increases because more RBCs pass through the alveolar capillaries in the same interval of time. In contrast, CO binds to Hb in such large amounts that no RBC spends enough time in an alveolar capillary to equilibrate P_Aco with P_c’co. Thus, the absorption of CO is diffusion limited, and simply increasing Q̇ will not necessarily increase CO uptake. Rather, the alveolar uptake of CO and other diffusion limited gases will more likely increase if S_A and S_C increase, or if τ_s decreases.

Normally O₂ has an intermediate equilibration rate to those of N₂O or CO. In healthy individuals, O₂ is a perfusion-limited gas over a wide range of Q̇ (Fig. 9.3), and at sea level alveolar O₂ uptake usually is not considered to be the rate-limiting step to maximal O₂ consumption, V̇o_2max (Chap. 12). However, in diseased lungs with destroyed or fibrotic alveolar septa, O₂ becomes diffusion limited during moderate exercise, and potentially at rest despite long RBC transit times. Even in healthy individuals, O₂ becomes a diffusion-limited gas when P_Ao₂ is reduced by a low F_Io₂ or by the reduced P_B at high altitude (Chap. 13).

Based on its greater aqueous solubility, CO₂ diffuses into and out of tissues ~20 times faster than O₂ per mm Hg of pressure gradient. Consequently, there is usually ample capillary transit time for CO₂ to achieve equilibrium despite its much smaller partial pressure gradient versus O₂. However, under conditions of reduced RBC transit time or with thickening of the alveolar septal membranes, CO₂ transfer may be incomplete and result in hypercarbia.

The long equilibration time of inhaled CO is used clinically to estimate the single-breath lung diffusing capacity for CO (DL_CO). As detailed in Chap. 16, this pulmonary function test is most often conducted on patients who are suspected of having reduced S_A or S_C, or increased τ_s. Subjects begin the maneuver at their RV and inhale gas with a low F_Ico (usually ~0.003) up to their TLC. Once at TLC, the breath is held for 10 seconds and then exhaled completely. Concentrations of CO in the exhaled gas are measured to establish F_Ēco and F_Éco (= F_Aco), and thus P_Aco by Dalton’s law. These data yield the CO uptake rate (V̇co) plus the “P₁” from the equation in Fig. 9.1 that drove its absorption. “P₂” in that same equation, being the subject’s P_Ćco, is considered zero since inhaled CO never equilibrates with blood in the capillaries. The diffusivity coefficient D_CO is constant because the aqueous solubility and mass of CO are known. DL_CO is computed then as:

where carbon monoxide conductance, C_CO = [D_CO · (S_A + S_C)]/(2 · τ_s). Thus, the working equation for the DL_CO test becomes:

Since all terms on the right side of this equation are measured by the single-breath DL_CO procedure, the test yields a robust “lump sum” or aggregate estimate of a subject’s alveolar and capillary surface areas available for diffusion, as well as their alveolar barrier’s thickness as an impediment to that diffusion. The subject’s measured value for DL_CO then can be compared with expected normative values like other spirometric data to assess the severity of emphysema, edema, interstitial fibrosis, or other disease processes that impact S_A, S_C, or τ_S.

It should be emphasized that despite crossing the alveolar-capillary membrane, O₂

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